The central role that p53 plays in preventing tumour development is clear although ongoing research continues to dissect the details of how exactly this is achieved. Furthermore, a role for p53 in development, longevity and overall fitness of an organism is starting to emerge (Vousden K H, Lane D P, Nat. Rev. Mol. Cell Biol., 2007 8 (4):275-83). p53 acts as a transcriptional regulator, inducing the expression of a range of anti-proliferative target genes. More than 50% of adult human tumours are characterised by inactivating mutations or deletions of the p53 gene. Other tumour types in which p53 is wild-type frequently have alterations in the mechanisms that control p53 activation. It is widely accepted that activation of the p53 tumour suppressor protein through the use of non-genotoxic compounds may prove therapeutically important.
One class of non-genotoxic p53 activators is known as the tenovins and exemplary compounds of this class are disclosed in WO 2008/029096 and by Lain, S. et al. (Cancer Cell, 2008, 13, 1-10). Tenovins function through inhibition of a group of NAD+-dependent protein deacetylases known as the sirtuins (HDAC class III) (Lain, S. et al. infra)). To date, one sirtuin family member SIRT1 is known to regulate p53 activity by deacetylating p53 at Lys382 (Vaziri H, Dessain S K. N g Eaton E. Imai S I. Frye R A. Pandita T K. Guarente L. Weinberg R A, Cell, 2001 107 (2): 149-59; and Luo J. Nikolaev A Y. Imai S. Chen D. Su F. Shiloh A. Guarentre L. Gue W., Cell, 2001 107 (2):137-48). Partly due to its ability to decrease p53 function, inhibiting SIRT1 is believed to represent an important target for cancer treatment (Lain, S. et al. (infra), Heltweg, B. et al. Cancer Res., 2006 66 (8), 4368-4377 and US 2005/0079995).
Additionally, inhibition of isoforms of SIRT1, particularly SIRT2, as well as SIRT1, are thought to represent an important target for p53 activation and thus cancer therapy (Smith et al., TRENDS in Cell Biology, 2002, 12(9), 404-406.
SIRT2, another of the sirtuins, is comparatively little studied vis-à-vis SIRT1 although, significantly, its inhibition has been linked with treatment for Parkinson's disease and other neurodegenerative disorders such as Huntington's disease (Outeiro T F, Kontopoulos E, Altmann S M, Kufareva I, Strathearn K E, Amore A M, Volk C B, Maxwell M M, Rochet J C, McLean P J, Young A B, Abagyan R, Feany M B, Hyman B T, Kazantsev A G. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science. 2007 Jul. 27; 317(5837):516-9; Luthi-Carter R, Taylor D M, Pallos J, Lambert E, Amore A, Parker A, Moffitt H, Smith D L, Runne H, Gokce O, Kuhn A, Xiang Z, Maxwell M M, Reeves S A, Bates G P, Neri C, Thompson L M, Marsh J L, Kazantsev A G. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci USA. 2010 Apr. 27; 107(17):7927-32. Epub 2010 Apr. 8). Moreover, Yun-Hye, J. et al. (Biochem. Biophys. Res. Commun., 2008, 368, 690-695) report that SIRT2 interacts with various of the seven isoforms of 14-3-3 proteins, which are highly conserved in nature, including mammals, and expressed in a wide range of tissue types and believed to play critical roles in various cellular mechanisms. Moreover it is also reported in this publication that SIRT2, like SIRT1, deacetylates p53, and down-regulates the transcriptional activity of p53. The inhibitory effect of SIRT2 on p53 is described as enhanced by the β and γ isoforms of 14-3-3. Furthermore, SirT2 inhibition has been suggested to contribute with SirT1 inhibition towards the activation of p53 (Peck B, Chen C Y, Ho K K, Di Fruscia P, Myatt S S, Coombes R C, Fuchter M J, Hsiao C D, Lam E W. SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol Cancer Ther. 2010 April; 9(4):844-55. Epub 2010 Apr. 6.) Accordingly, in addition to being useful in the treatment of neurodegenerative diseases such as Parkinson's; it is reasonable to postulate that inhibitors of SIRT2, like inhibitors of SIRT1, will allow the development of treatments for diseases associated with abnormalities or deficiencies with the p53 pathway including cancers and other hyperproliferative disorders. Furthermore, SirT2 is clearly involved in the modulation of tubulin acetylation (North B J, Marshall B L, Borra M T, Denu J M, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol. Cell. 2003 February; 11(2):437-44). Because tubulin integrity is essential for cell migration and correct cell cycle progression, compounds that interfere with tubulin function (i.e. tubulin poisons) are well established anticancer agents. Therefore SirT2 inhibitors, through their capacity to increase levels of acetylated tubulin, interfere with tumour cell migration and proliferation.
There remains a need for the development of additional inhibitors, of sirtuins, for example SIRT1 and SIRT2, in particular inhibitors that are selective towards SIRT2 over other sirtuins.